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Liver stage malaria infection is controlled by host regulators of lipid peroxidation.

ABSTRACT: The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with the production of reactive oxygen species, lipid peroxidation, and a form of cell death called ferroptosis, plays a critical role in control of Plasmodium liver stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces Plasmodium liver stage parasite infection. In contrast, blocking negative regulators of this pathway, NOX1 and TFR1, leads to an increase in liver stage infection. We have shown previously that increased levels of P53 reduces Plasmodium LS burden in an apoptosis-independent manner. Here, we demonstrate that increased P53 is unable to control parasite burden during NOX1 or TFR1 knockdown, or in the presence of ROS scavenging or when lipid peroxidation is blocked. Additionally, SLC7a11 inhibitors Erastin and Sorafenib reduce infection. Thus, blocking the host SLC7a11-GPX4 pathway serves to selectively elevate lipid peroxides in infected cells, which localize within the parasite and lead to the elimination of liver stage parasites.

SUBMITTER: Kain HS

PROVIDER: S-EPMC7206113 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Liver stage malaria infection is controlled by host regulators of lipid peroxidation.

Kain Heather S HS Glennon Elizabeth K K EKK Vijayan Kamalakannan K Arang Nadia N Douglass Alyse N AN Fortin Chelsea L CL Zuck Meghan M Lewis Adam J AJ Whiteside Samantha L SL Dudgeon Denali R DR Johnson Jarrod S JS Aderem Alan A Stevens Kelly R KR Kaushansky Alexis A

Cell death and differentiation 20190507 1

The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with the production of reactive oxygen species, lipid peroxidation, and a form of cell death called ferroptosis, plays a critical role in control of Plasmodium liver stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces Plasmodium liver stage parasite infection. In contrast, blocking negative regulators of this pathway, NOX1 ...[more]

PMID: 31065106

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Project description:After entering their mammalian host via the bite of an Anopheles mosquito, Plasmodium sporozoites migrate to the liver where they traverse several hepatocytes before invading the one inside which they will develop and multiply into thousands of merozoites. Although this constitutes an essential step in malaria infection, the requirements of Plasmodium parasites in liver cells and how they use the host cell for their own survival and development are poorly understood. To gain new insights into the molecular host-parasite interactions that take place during malaria liver infection, we have used high-throughput microarray technology to determine the transcriptional profile of P. yoelii-infected hepatocytes that were collected from P. yoelii-infected mice 24 and 40 h after infection. This in vivo microarray expression was compared with the microarray analysis of in vitro infected hepatoma cells infected with closely related rodent malaria parasite P. berghei. Differential expression patterns for host genes identify genes and pathways involved in the host response to rodent Plasmodium parasites. Keywords: gene expression Total RNA from sorted liver stage (LS) infected hepatocytes were isolated from PyGFP-infected BALB/c mice as described in Tarun et al (2008). RNA from LS-infected hepatocytes were isolated at two time points post-infection (pi): 24 hr pi (LS24) and 40 hr pi (LS40). As control, RNA from hepatocytes isolated from mock-infected mice (infected with salivary gland extract) at the same time points was also isolated following the same procedure. Total RNA was then subjected to two rounds of linear amplification using the Amino Allyl Message Amp II aRNA Amplification Kit (Ambion) according to manufaturerâs directions. The quality of total and amplified RNAs were examined with the Agilent 2100 BioanalyzerTM (Agilent Technologies) and the quantity of the RNA samples was assessed using a Nanodrop ND-1000 spectrophotometer prior to microarray hybridization. For each timepoint two independent biological replicates were obtained.

Dataset Information

Liver stage malaria infection is controlled by host regulators of lipid peroxidation.

Publications

Liver stage malaria infection is controlled by host regulators of lipid peroxidation.

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